Regulation of Glycolysis by Non-coding RNAs in Cancer: Switching on the Warburg Effect

Abstract

The "Warburg effect" describes the reprogramming of glucose metabolism away from oxidative phosphorylation toward aerobic glycolysis, and it is one of the hallmarks of cancer cells. Several factors can be involved in this process, but in this review, the roles of non-coding RNAs (ncRNAs) are highlighted in several types of human cancer. ncRNAs, including microRNAs, long non-coding RNAs, and circular RNAs, can all affect metabolic enzymes and transcription factors to promote glycolysis and modulate glucose metabolism to enhance the progression of tumors. In particular, the 5'-AMP-activated protein kinase (AMPK) and the phosphatidylinositol 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) pathways are associated with alterations in ncRNAs. A better understanding of the roles of ncRNAs in the Warburg effect could ultimately lead to new therapeutic approaches for suppressing cancer.

Keywords: Warburg effect; cancer; glycolysis; non-coding RNAs.

Graphical abstract

Figure 1

Mechanism of miRNA Biogenesis miRNAs are initially transcribed as a long 5′-capped and 3′-polyadenylated pri-miRNA. The Drosha complex transforms the pri-miRNA into a hairpin-shaped pre-miRNA. Exportin-5 exports the pre-miRNA into the cytoplasm, where it is further processed by Dicer. The double-stranded miRNA is dissociated, and the mature miRNA strand is combined in the RISC where it carries out gene silencing by increasing the degradation of target mRNAs or by translational inhibition.

Figure 2

lncRNAs Regulate Some Molecules Involved in Glucose Metabolism in Cancer lncRNAs regulate glucose uptake and glycolytic flux by modulating GLUTs and glycolytic enzymes. This figure was adapted from Fan et al.

Figure 3

Role of PI3K/AKT/mTOR, LKB1-AMPK, and lncRNA-mediated HIF in Glucose Metabolism in Tumor Cells The stability and synthesis of HIF-1α protein can be affected by lncRNAs, thus modulating HIF-1-mediated metabolic reprogramming. In cancer cells, the translation of HIF-1a mRNA is dependent on the activity of the mammalian target of rapamycin (mTOR) governed by the activity of upstream tumor suppressor proteins and oncoproteins. HIF-1α plays a key role in blocking mitochondrial activity and stimulating glycolic enzymes. lncRNAs can also regulate the Akt and AMPK pathways. Akt may increase oxidative phosphorylation by enhancing metabolic coupling between glycolysis and oxidative phosphorylation, through facilitating the association of mitochondrial hexokinase with VDAC in the mitochondria. Akt enhances glycolytic flux via several mechanisms. First, it increases glucose uptake and flux. Second, hyperactivated Akt activates mTORC1, which promotes HIF-1α accumulation under normoxic conditions and increases levels of GLUT1, HKII, and lactate dehydrogenase (LDH). Finally, Akt-increased cellular ATP levels help to maintain low AMPK activity, which is required for full activation of mTORC1. This figure was adapted from Fan et al.